Androstendione and a method of producing the same



. Patented on. 10, 939

ANDROSl'END IONE AND A METHOD PRO-DUCING.THE SAME walter Schoeller, Berlin-Westend, and Arthur Serini and Willy Logemann, Berlin, Germany, assignors to Schering Aktiengesellschaft, aigorporation of Germany NoDrawing. Application September28, 1935,

Serial No. 42,572. In Germany October 4,,

. 26 Claims. (Cl. 260-397) This invention relatesto an unsaturated diketone of the cyclopentano polyhydro ,phenanthrene series, and more particularly to .andros tendione and a method of producing the same.

()ne object of this invention is the production of the diketone androstendione from the corre-l sponding hydroxy ketones androstenolonejs by subjecting the latter to the action of suitable oxidizing or dehydrogenating agents.

Another object of this invention is the transformation of the hydroxy ketone dehydroandrosterone into said diketone androst'endione.

- ,Said starting materials, the androstenolones correspond to the general formula CmHzaQz' and the structural formula wherein the. =0-group may be. at the C-atom' 3 or 1'7 and the hydroxy group at the C-atom 1'7 or 3 respectively. These compounds have been isolated from natural sources such as testicles or the urine of male individuals, or have been produced synthetically, for-instance, by oxidizing sterols,' or the like methods. They show a remarkable physiological activity in the caponcomb test as well as in the vesicular gland test. The new product androstendione, obtained ac- CH2. CH:

It is known also as A' -etiocholene-dione(3,17).

Since thisdiketone has a physiological activity that is considerably higher thanQtor instance, that of dehydr0androsterone,' i. e. the andro stenol 3)-one-('17), the processdescribed and claimed hereinafter makes itpossible to transmore;

form. this, latter'natui al product into a active synthetic compound.

The oxidation process-may be carried out by.-

treating the androstenolones with oxidising a them:

' or benzine whereby crystals cording, to this invention corresponds to the general formula C19H2s02 and the structural formula agents which, do not attach the double bond or by first protecting the double bond, for example,

-lishing the double bond in the oxidation product by adding on halogenv or halogen 'hydrideflsub- .se'quently oxidising to the ketone and---reestab-' obtained. The treatment with halogen or halogen hydride yields a saturated intermediate'compound havingsubstituents in-the 5 and 6 positions of which one is halogen and the other halogen or hydrogen.

The following examplesserve to illustratethis invention without, however, limiting the same-t0 Example 1 i 2 grams of androstenol-(3)-one-(17) are dissolved in 100 cc. of glacial acetic acid.- To this solution isadded at room temperature a' solution 011.1 grams of bromine in 30 cc. ofglacial acetic acid while stirring. As soon as the solution has become colorless, 1.0 gram of chromic acid anhydride in 10 cc. of 80% acetic acid are gradually added thereto. The reaction'mixture is-allowed to stand for 1 to 2 days. Thereupon 5 grams of zinc dust are added, and. the mixture is vigor,-

ously stirred for 12 hours at room temperature. The solution is filtered, the filtrate poured into 1 to 2- liters of water, neutralized with dilute sodium hydroxide solution in the cold, 'extracted with ether, the ethereal solution is washed with dilute sodium hydroxide solution and water, and the ether is evaporated. The residue is recrystallized from dilute alcohol, acetic acid ethyl ester,

169-170 C. are obtained.

Example 2 v1 gram of androstenolone is dissolved in cc. of carbontetrachloride and to this solution a solution of'-0.25 gram of chlorine in. 25 cc. of carbon tetrachloride is added drop by drop at room temperature. Thereupon the carbon tetrachloride is evaporated in a vacuum, the residue is dissolved in 100 cc. of glacial acetic acid and oxidized by adding a'solution of 0.5 gram of chromlc acid anhydride. in 10 cc. of acetic acid. The'working up and 'dechlorination of the oxidationtproduct is carried out in the same manher as described in Example 1'.

Example 3 2igrams of androstenolone are dissolved in cc. of'a mixture of equal parts of ether and absolute alcohol. Into this'solution 40. grams of dry hydrochloric acidgas are introduced and the reaction nixtureis allowed to stand for 1 to 2 of the melting point days in the cold. 'Ihereupon the ether is evaporated at a very low temperature in a vacuum, the

precipitatedandrostenolone hydrochloride is 111- tered by suction, dissolved in glacial .acetic acid and oxidized withg0.6 gram of chomic acid anhydride in glacial acetic acid.- After oxidation most of the acetic acid is evaporated in a.

high vacuum whereby the temperature is kept as low as possible.- 'me residue is heated with pyridine under reflux to boiling in order, to split ofl hydrochloric acid. The reaction solution is then poured into dilute sulfuric acid, extracted with ether and the ethereal-solution is washed with dilute alkali lye and water. .After drying, it is evaporated to dryness, the residue is purified by recrystallisation and yields the same androstendione as described in the preceding examples.

. Example! The brominated' androstenolone as obtained, for instance, according to the method described in Example 1, is dissolved in 100 cc. of benzene. The benzene solution is shaken with 40 cc. of 4% Example 5 '1 gram'of androstenolone is fused in a widemouthed test tube and heated at an outside temperature of about 280 C. 5 grams of finely powdered, copper oxide are introduced into the fused mass in several portions. After further heating for 1 hour it is cooled and the reaction product shaken with animal charcoal and the ether evaporated. From the residue the androstendione, as described in the preceding examples, is isolated.

Ofcourse, many changes andvariations may be made in the reaction conditions described in the above given examples. Thus, for instance, the halogenation oi the starting materialsmay not only be carried'out in glacial acetic acid or in carbon tetrachloride, but alsoother organic solvents which are not substantially aifected by halogen may be used likewise, such as chloroform and the like.

.The splitting oil! of hydrogen halide or halogen in order to establish a double ,bond in the ring system is achieved not only by those reagents mentioned in the examples, as by treatment w th pyridinebases or with zinc dust also other reagents may be used such as treatment with alkaline agents or the like, i. e. methods as they are described, for instance, by Houben Die Methoden der organischen Chemie", 2d edition, vol. 2, P es 744- 146 (1922).

The oxidation of the androstenolones may not only be carried out by means of chromic acid anhydride or potassium permanganate but also other oxidizing agents capable of transforming a hydroxy group into a keto group, such as bichromates in acid solution, alkali and alkaline earth permanganates, metal oxides and the like.

The separation and isolation of the halogenated intermediate compounds and the unsaturated end product is not only made in the manner described in the examples for instance, by extracting the reaction mixtures with suitable solvents and evaporating the latter, or by precipitating the com extracted with ether, the ethereal solution is respectively, but

pounds iormed from their solutions by means of water or other organic solvents wherein they are insoluble, while the by-products and impurities remain dissolved therein, but one may also use other methods, for instance, by making use of the formation of insoluble or difllcultly soluble condensation products as with typical ketone reagents and the like.

The purification of said intermediate and end products may be done by fractional and/or repeated crystallisation, distillation, sublimation and the like.

Of course, the amounts of the various agents and the type and the amount of the solvents used in carrying out this invention, the temperatures employed and other reaction conditions may be varied within the limits obvious to'those skilled in the art. Hence, many other changes and variations may be made in accordance with the prin-' ciples set forth herein and hereto. 7

What we claim is:

in the claims annexed 1. A method for producing an androstend ione of the general formula CinHasOz, comprising oxidizing an androstenolone of thegeneral formula CioHraO: with an agent capable of converting a secondary alcohol group into a keto group.

2. A method for producing an androstendione of the general formula CioHzsOr, comprising oxidizing an androstenolone of the general formula CmHzaO: with an agent capable of converting a secondary alcohol group into a keto group, and isolating the diketone obtained.

3.- A method according to claim 2, wherein an oxidizing agent is used which does not. attack the double bond in the molecule of the starting .material.

4. A method according to claim '2, including the step of adding a member of the group consisting of halogen and halogen hydride, at the double bond, to protect the same during oxidation against the action of the oxidizing agent.

. 5. A method'according to claim 2, wherein the double bond is intermediate addition of halogen to'the double protected during oxidation by bond. v v

I 6. A method according to claim 2, wherein the double bond is protected during oxidation by intermediate addition of halogen hydride to the double bond.

7. A method according to claim 2, wherein as oxidizing agent chromic acid anhydride is used.

8. A method for producing an androstendione of the general formula CnHasOa, comprising oxidizing dehydroandroste'rone of the general formula CisHsaOa and the structural formula I OH;

convertinga secondary group, and isolating the with an agent capable of alcohol group into a keto diketone obtained.

9. A method for producing an androstendione of the general formula Ci'oHasOz, comprising treating an androstenolone of the general'formula CisHaO: with a member of the group consisting of halogen and halogen hydride, so as to saturate the double bond-in the molecule of said starting material-oxidizing the halogenated compound obtained with an agent capable of converting a secondary alcohol group into a keto group, reacting the oxidized product with an agent capable of splitting. oil! said member and thereby reestablishing the double bond in the oxidized compound, and isolating the unsaturated diketone obtained.

10. A method according to claim 9, in which halogen is added at the double bond by treating a solution of the unsaturated androstenolone with halogen.

11. A method according to claim 9, in which halogen hydride is added at the double bond by treating a solution of the unsaturated androstenolone with halogen hydride.

12. A method according to claim 9, in which halogen is added at the double bond by treating a solution of the unsaturated androstenolone with j halogen, and wherein the splitting of! of the halogen added is eflected by reacting the halogenated compound with zinc.

13. A method according to claim 9, in which a hexavalent chromium compound is used as oxidizing agent which is capable of effecting the aforementioned conversion.

14. A halogenated androstenone compound of the general formula CreHasOXYZ corresponding to the structural formula CH: CH: O

at least one of the x and Y groups being halogen and the other a member of the group consisting of halogen and hydrogen, and Z is a divalent group selected from the crops consisting of ketonic O and on O and Z being attached to the 3 and 17 carbons inany order.

15. .A halogenated androstendione oi the gen-- eral. formula CuHaOaXY formula and the structural wherein at least one of the X and Y groups is halogen and the other a member of the group consisting of halogen and hydrogen.

16.- A halogenated 'androstenol-(S) -one-(17) of the general formula C19H2aO2XY and the structural formula a no wherein at least one of the X and Y groups is halogen and the other a member of the group consisting of halogen and hydrogen.

17. A -etiocholene-dione- (3,17)

18. A process for producing A -etiocholene- 23. The dibromide of A -etiocholene-dione- (3,17). l

24. In a process for producing an androsten- 'dione compound; the step which comprises treating an androstenolone compound having a free secondary alcohol group with arr-oxidizing agent capable of converting such group into a keto group.

25. In a process for producing A -etiocholenedione-(3,1'7),,the steps which comprise reacting a dehydroandrosterone compound with an agent capable of oxidizing the hydroxy group to a keto group, and separating the M -etiocholene-dione- (3,17) from the reaction product.

26. A A unsaturated polyketone of the etiocholane series having keto groups in the 3 and 17 positions.

ARTHUR SERINI. WILLY LOGEMANN.

wan-ma sono ram; 

